The proposed project is designed to expand on the recent observations that the activity and state of phosphorylation of rat hepatic phenylalanine hydroxylase can be altered in response to glucagon administration. These findings suggest that agents and/or physiological conditions that result in altered cyclic AMP and/or protein kinase levels can regulate phenylalanine hydroxylase activity in vivo. The primary objective of this project is to study the modulation of activity and the multiple forms of rat liver phenylalanine hydroxylase by alterations in the circulating levels of insulin, glucagon, catecholamines and, perhaps, glucocorticoids. In particular the effects of varying the insulin/glucagon ratio is to be examined. In addition, any resultant effect on: (a) plasma levels of phenylalanine and tyrosine; (b) dihydropteridine reductase activity; (c) phenylalanine aminotransferase activity and (d) gluconeogenesis from phenylalanine will be examined. A secondary objective is to examine the state of phosphorylation of phenylalanine hydroxylase from rats under experimental phenylketonuria conditions and also to examine the effects of hormones, etc., under those conditions.